Pyrazole derivative

ABSTRACT

Drugs, in particular, pyrazole derivatives represented by the following general formula (I) which have a calcium release-dependent calcium channel inhibitory effect and medicinal compositions, in particular, calcium release-dependent calcium channel inhibitors containing the above compounds as the active ingredient,  
                 
(in the formula, each symbol has the following meaning: B: phenylene, a nitrogen-containing, divalent, saturated ring group, or a monocyclic, divalent heteroaromatic ring group which may be substituted with Alk, 
     X: —NR 1 —CR 2 R 3 —, —CR 2 R 3 —NR 1 —, —NR 1 —SO 2 —, —SO 2 —NR 1 — or —CR 4 ═CR 5 —, and A: benzene ring which may have one or more substituents; mono-, di- or tricyclic fused heteroaryl which may have one or more substituents; cycloalkyl which may have one or more substituents; a nitrogen-containing, saturated ring group which may have one or more substituents; lower alkenyl which may have one or more substituents; lower alkynyl which may have one or more substituents; or Alk which may have one or more substituents).

TECHNICAL FIELD

This invention relates to a medicament, particularly a pyrazolederivative having an action to inhibit calcium release-dependent calciumchannel, and a pharmaceutical composition containing the same as anactive ingredient, particularly a calcium release activated calciumchannel inhibitor.

BACKGROUND ART

It has been known for a long time that calcium ion (Ca²⁺) is importantfor an intracellular second messenger in the activation of variouscells. Intracellular Ca²⁺ also acts as an important regulatory factor ininflammatory cells. It has been suggested, however, thatvoltage-operated Ca²⁺ channel (to be referred to as “VOCC” hereinafter)inhibitors such as nifedipine does not show inhibitory activity againstthe activation of inflammatory cells and that a Ca²⁺ influx mechanismother than VOCC exist in inflammatory cells.

Hoth et al. have reported that a Ca²⁺-selective and Ca²⁺ storedepletion-activated Ca²⁺ channel, namely Ca²⁺ release-activated Ca²⁺channel (to be referred to as “CRACC” hereinafter; also calledstore-dependent Ca²⁺ channel), is present in mast cells and lymphocytes,and these cells are insensitive to membrane potential (Pflugers Arch.,430, pp. 315-322 (1995)). It is known that CRACC is present in severalinflammatory cells such as mast cells, lymphocytes, astrocytes (J. Biol.Chem., 270, pp. 29-32 (1995)) and the like, and that it is deeplyconcerned in, for example, cytokine production and lipid mediatorrelease (J. Immunol., 155, pp. 285-296 (1995) and Br. J. Pharmacol.,114, pp. 598-601 (1995)).

Recently, it has been revealed that tenidap, an agent for treatingrheumatoid arthritis, has a potency of CRACC inhibitor (Cell Calcium,14, pp. 1-16 (1993)). Therefore, a CRACC inhibitor has a possibility oftherapeutic potency on chronic inflammatory diseases includingrheumatoid arthritis.

It is known that CRACC is also present in endothelial cells (Am. J.Physiol., 269, C 733-738 (1995)) and epithelial cells (J. Biol. Chem.,270, pp. 29169-175 (1995)). Since it has been reported that sustainedcalcium influx takes a role in the radical affection of endothelialcells (Am. J. Physiol., 261, C 889-896 (1991)), it is suggested that aCRACC inhibitor should have protective efficacy on endothelialcell-concerned tissue damage.

In addition, it has been reported that blockades of calcium influxinhibit cell proliferation and interleukin 2 (IL-2) production (Br. J.Pharmacol., 113, pp. 861-868 (1994)). Therefore, a CRACC inhibitor isuseful as an agent for the prevention and treatment of proliferative orprogressive diseases (e.g., malignant tumor and the like) and autoimmunediseases, and also as a suppresser for tissue rejection intransplantation.

On the other hand, it is known that in excitable cells such as smoothmuscle cells and nerve cells, intracellular calcium is mainly regulatedwith VOCC not with CRACC. Therefore, it is expected that a calciumchannel blocker having CRACC selectivity against VOCC should be anuseful agent for the prevention or treatment of various inflammatorydiseases, allergic diseases, autoimmune diseases, tissue damages,proliferative diseases and the like without undesirable actions oncardiovascular and central nervous system.

Recently, some compounds showing CRACC inhibitory activity have beenreported, such as a cycloalkyl-piperazinylethanol derivative disclosedin a published German patent application 4404249 and a2-(3,4-dihydro-1-isoquinolyl)acetamide derivative disclosed in WO94/00435. It has also reported that5-amino-1-[[3,5-dichloro-4-(4-chlorobenzoyl)phenyl]methyl]-1H-1,2,3-triazole-4-carboxamideinhibits CRACC (J. Pharm. Exp. Ther., 257, pp. 967-971 (1991)). However,there are no reports on a compound whose CRACC selectivity over VOCC hasbeen confirmed.

On the other hand, a published German patent application 2525024discloses a 5-(heterocycloylaminophenyl)-1-phenylpyrazole derivativewhich shows an anti-inflammatory activity. However, this patent does notdisclose or suggest about its inhibitory activities against CRACC andIL-2 production.

WO 95/18097 discloses an anthranilic acid derivative represented by thefollowing formula (I), which inhibits a cyclic GMP phosphodiesterase. Inthe formula, R₁ to R₄ represent H, a halogen atom, . . . , pyrazolylwhich may be substituted, . . . ; n is 0 to 6, W represents N or CH, Yrepresents O or S, . . . (see said published patent application fordetails).

An unexamined published Japanese patent application 9-59236 discloses anR¹, R²-di-substituted benzamide derivative represented by the followingformula (1), which is useful for the prevention and treatment ofrheumatic, allergic and other inflammatory diseases. In the formula, R¹represents a substituted or unsubstituted aromatic heterocyclic ring, .. . , R² represents a halogen, a nitro, —NR⁵R⁶, . . . , A represents—C(=Z)NR³R⁴ or —NR⁴C(=Z)R³, R³ represents a substituted or unsubstitutedaromatic hydrocarbon ring, a substituted or unsubstituted aromaticheterocyclic ring . . . (see said published patent application fordetails). However, there is no illustrative disclosure about pyrazolylas the aromatic heterocyclic ring group. In addition, there is nodisclosure about inhibitory activities against CRACC and/or IL-2production.

DISCLOSURE OF THE INVENTION

The inventors of the present invention have conducted extensive studieson the screening of compounds having excellent CRACC inhibitoryactivity. As a result of the efforts, certain pyrazole derivatives whichpossess entirely different structures from those of the reported CRACCinhibitors have been found to show excellent CRACC inhibitory activity.The present invention has been accomplished by further finding thatthese compounds have high CRACC selectivity over VOCC.

Accordingly, the invention relates to a novel pyrazole derivativerepresented by the following general formula (I) which is characterizedin that it has a pyrazolyl group unsubstituted or substituted with aspecified group, or a pharmaceutically acceptable salt thereof. In thespecification of this application, lower alkyl and halogen atom areabbreviated as Alk and Hal, respectively.

(In the formula, each symbol has the following meaning:

-   D: pyrazolyl which may have 1 to 3 substituents selected from the    group consisting of -Alk, -lower alkenyl, -lower alkynyl,    -halogeno-lower alkyl, -Alk-cycloalkyl, -Alk-O-Alk, -cycloalkyl,    —O-Alk, —COOH, —COO-Alk and -Hal,-   n: 0 or 1,-   B: phenylene, a nitrogen-containing, divalent, saturated ring group,    or a monocyclic, divalent heteroaromatic ring group which may be    substituted with Alk,-   X: —NR¹—CR²R³—, —CR²R³—NR¹—, —NR¹—SO₂—, —SO₂—NR¹— or —CR⁴═CR⁵—,-   R¹: —H, —OH, -Alk, —O-Alk or —CO-Alk,-   R² and R³: the same or different from each other and each represents    —H or -Alk, or R² and R³ together form ═O or ═S,-   R⁴ and R⁵: the same or different from each other and each represents    —H, -Hal, -halogeno-lower alkyl or -Alk, and-   A: benzene ring which may have one or more substituents; mono-, di-    or tricyclic fused heteroaryl which may have one or more    substituents; cycloalkyl which may have one or more substituents; a    nitrogen-containing, saturated ring group which may have one or more    substituents; lower alkenyl which may have one or more substituents;    lower alkynyl which may have one or more substituents; or Alk which    may have one or more substituents,    or A and X may together form a group represented by a formula    (wherein A² is a nitrogen-containing hetero ring selected from the    group consisting of 1-pyrrolidinyl, pyrazolidinyl, piperidino,    piperazinyl, morpholino, 3,4-dihydro-2H-1,4-benzoxazin-4-yl and    indolinyl, wherein the hetero ring may have one or more    substituents),    with the proviso that-   (1) when D is 3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl, n is 0, B is    1,4-phenylene and X is NHCO, A is a group other than    4-methyl-1,2,3-thiadiazol-5-yl,-   (2) when D is 1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl, n is 0, B    is thiophene-2,5-diyl and X is CONH, A is a group other than    4-chlorophenyl,-   (3) when D is 1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl, n is 0, B    is thiophene-2,5-diyl and X is CONH, A is a group other than benzyl,-   (4) when D is 4-ethoxycarbonyl-5-trifluoromethyl-1H-pyrazol-1-yl, n    is 0, B is 1,4-phenylene and Y is NHCO, A is a group other than    trichlorovinyl,-   (5) when D is 1H-pyrazol-1-yl, n is 0, B is 1,4-phenylene and Y is    NHCO, A is a group other than 2-ethoxyvinyl, and-   (6) when n is 1, D is 1H-pyrazol-5-yl substituted with at least one    trifluoromethyl group or 1H-pyrazol-1-yl substituted with at least    one trifluoromethyl group. The same shall apply hereinafter.)

The invention also relates to a pharmaceutical composition, particularlya pharmaceutical composition for use in the inhibition of calciumrelease-dependent calcium channel, which comprises a pyrazole derivativerepresented by the following general formula (I′) or a pharmaceuticallyacceptable salt thereof and a pharmaceutically acceptable carrier.Preferably, it relates to an IL-2 production inhibitor, a preventive ortherapeutic agent for allergic, inflammatory or autoimmune diseases anda preventive or therapeutic agent for bronchial asthma or rheumatoidarthritis.

(In the formula, each symbol has the following meaning:

-   D: pyrazolyl which may have 1 to 3 substituents selected from the    group consisting of -Alk, -lower alkenyl, -lower alkynyl,    -halogeno-lower alkyl, -Alk-cycloalkyl, -Alk-O-Alk, -cycloalkyl,    —O-Alk, —COOH, —COO-Alk and -Hal,-   n: 0 or 1,-   B: phenylene, a nitrogen-containing, divalent, saturated ring group,    or a monocyclic, divalent heteroaromatic ring group which may be    substituted with Alk,-   X: —NR¹—CR²R³—, —CR²R³—NR¹—, —NR¹—SO₂—, —SO₂—NR¹— or —CR⁴═CR⁵,-   R¹: —H, —OH, -Alk, —O-Alk or —CO-Alk,-   R² and R³: the same or different from each other and each represents    —H or -Alk, or R² and R³ together form ═O or ═S,-   R⁴ and R⁵: the same or different from each other and each represents    —H, -Hal, -halogeno-lower alkyl or -Alk, and-   A: benzene ring which may have one or more substituents; mono-, di-    or tricyclic fused heteroaryl which may have one or more    substituents; cycloalkyl which may have one or more substituents; a    nitrogen-containing, saturated ring group which may have one or more    substituents; lower alkenyl which may have one or more substituents;    lower alkynyl which may have one or more substituents; or Alk which    may have one or more substituents,    or A and X may together form a group represented by a formula    (wherein A² is a nitrogen-containing hetero ring selected from the    group consisting of 1-pyrrolidinyl, pyrazolidinyl, piperidino,    piperazinyl, morpholino, 3,4-dihydro-2H-1,4-benzoxazin-4-yl and    indolinyl, wherein the hetero ring may have one or more    substituents), with the proviso that when n is 1, D is    1H-pyrazol-5-yl substituted with at least one trifluoromethyl group    or 1H-pyrazol-1-yl substituted with at leaset one trifluoromethyl    group. The same shall apply hereinafter.)

The following known compounds are included in the aforementioned generalformula (I′).

-   (1) A compound wherein D: 3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl,    n: 0, B: 1,4-phenylene, Y: NHCO and A:    4-methyl-1,2,3-thiadiazol-5-yl (to be referred to as compound A    hereinafter),-   (2) a compound wherein D:    1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl, n: 0, B:    thiophene-2,5-diyl, Y: CONH and A: 4-chlorophenyl (to be referred to    as compound B hereinafter),-   (3) a compound wherein D:    1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl, n: 0, B:    thiophene-2,5-diyl, Y: CONH and A: benzyl (to be referred to as    compound C hereinafter),-   (4) a compound wherein D:    4-ethoxycarbonyl-5-trifluoromethyl-1H-pyrazol-1-yl, n: 0, B:    1,4-phenylene, Y: NHCO and A: trichlorovinyl (to be referred to as    compound D hereinafter), and-   (5) a compound wherein D: 1H-pyrazol-1-yl, n: 0, B: 1,4-phenylene,    Y: NHCO and A: 2-ethoxyvinyl (to be referred to as compound E    hereinafter).

However, though the compounds A to D are described in the MAYBRIDGE'sreagent catalog (UK, Cornwall, published in August, 1995) as SEW04225,KM02940, KM03000 and GK02421, there are no reports on their applicationto not only medicaments as a matter of course but also other use. Also,the compound E is disclosed as a production material of a medicament inJP-A-61-82, but there is no description regarding its pharmacologicalactions. Thus, the pharmaceutical compositions which contain these knowncompounds are novel.

Preferred compounds of the general formula (I) or (I′) of the inventionare pyrazole derivatives or pharmaceutically acceptable salts thereof,in which the pyrazolyl group of D is pyrazolyl (particularly1H-pyrazol-5-yl or 1H-pyrazol-1-yl) which is substituted with at leastone trifluoromethyl group.

Other preferred compounds of the invention are listed below.

Pyrazole derivatives or pharmaceutically acceptable salts thereof, inwhich

-   1) A is phenyl which may have one or more substituents of F group;    mono-, di- or tricyclic fused heteroaryl which may have one or more    substituents of F group; cycloalkyl which may have one or more    substituents of F group; a nitrogen-containing, saturated ring group    which may have one or more substituents of F group; lower alkenyl    which may have one or more substituents of G group; lower alkynyl    which may have one or more substituents of G group; or Alk which may    have one or more substituents of G group, wherein-   the F group is a group consisting of -Alk, -lower alkenyl, -lower    alkynyl, -Hal, —NH₂, —NH(Alk), —N(Alk)₂, —NO₂, —CN, —OH, —O-Alk,    —O—CO-Alk, —SH, —S-Alk, —COOH, —COO-Alk, —CO-Alk, —CHO, —CONH₂,    —CONH(Alk), —CON(Alk)₂, —SO-Alk, —SO₂-Alk, —SO₂NH₂, —SO₂NH-(Alk),    —SO₂N(Alk)₂, -aryl, -cycloalkyl, —O-Alk-O—, -halogeno-lower alkyl,    -Alk-NH₂, -Alk-NH(Alk), -Alk-N(Alk)₂, -Alk-OH, -Alk-O-Alk, -Alk-SH,    -Alk-S-Alk, -Alk-COOH, -Alk-COO-Alk, -Alk-CO-Alk, -Alk-CHO,    -Alk-CONH₂, -Alk-CONH(Alk), -Alk-CON(Alk)₂, -Alk-SO-Alk,    -Alk-SO₂-Alk, -Alk-SO₂NH₂, -Alk-SO₂—NH(Alk), -Alk-SO₂N(Alk)₂,    -Alk-aryl and -Alk-cycloalkyl, and the G group is a group consisting    of -Hal, —NH₂, —NH(Alk), —N(Alk)₂, —NO₂, —CN, —OH, —O-Alk,    —O—CO-Alk, —SH, —S-Alk, —COOH, —COO-Alk, —CO-Alk, —CHO, —CONH₂,    —CONH(Alk), —CON(Alk)₂, —SO-Alk, —SO₂-Alk, —SO₂NH₂, —SO₂NH-(Alk),    —SO₂N(Alk)₂, aryl which may have one or more substituents of F    group; mono-, di- or tricyclic fused heteroaryl which may have one    or more substituents of F group; cycloalkyl which may have one or    more substituents of F group and a nitrogen-containing, saturated    ring group which may have one or more substituents of F group,    or A and X may together form a group represented by a formula    (wherein A² is a nitrogen-containing hetero ring selected from the    group consisting of 1-pyrrolidinyl, pyrazolidinyl, piperidino,    piperazinyl, morpholino, 3,4-dihydro-2H-1,4-benzoxazin-4-yl and    indolinyl, wherein the hetero ring may have one or more substituents    of F group),-   2) B is phenylene; piperidine-1,4-diyl; or a monocyclic, divalent    heteroaromatic ring selected from the group consisting of thiophene,    furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole,    isoxazole, thiadiazole, pyridine, pyrazine, pyridazine and    pyrimidine, which may be substituted with Alk, X is —NH—CO—,    —NH—CH₂—, —N(OH)—CO—, —N(Alk)-CO—, —CO—NH—, —CH₂—NH—, —CO—N(OH)—,    —CO—N(Alk)-, —SO₂NH—, —NHSO₂— or —CH═C(Hal)-, A is aryl which may    have one or more substituents of group F; mono-, di- or tricyclic    fused heteroaryl selected from the group consisting of thienyl,    furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl,    oxazolyl, isoxazolyl, tetrazolyl, triazolyl, thiadiazolyl, pyridyl,    pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl,    isoquinolyl, quinolyl, quinoxanyl, phthalazinyl, imidazopyridyl,    quinazolinyl and cinnolinyl, which may have one or more substituents    of group F; cycloalkyl; a nitrogen-containing, saturated ring    selected from the group consisting of pyrrolidinyl, imidazolidinyl,    pyrazolidinyl, piperidyl, piperazinyl and morpholinyl, which may be    substituted with one or more Alk; lower alkynyl which may be    substituted with one or more Hal; lower alkenyl which may be    substituted with one or more Hal; or Alk which may be substituted    with one or more Hal, and the F group is a group consisting of -Alk,    -lower alkenyl, -lower alkynyl, -Hal, —NH₂, —NH(Alk), —N(Alk)₂,    —NO₂, —CN, —OH, —O-Alk, —O—CO-Alk, —SH, —S-Alk, —COOH, —COO-Alk,    —CO-Alk, —CHO, —CONH₂, —CONH(Alk), —CON(Alk)₂, —SO-Alk, —SO₂-Alk,    —SO₂NH₂, —SO₂NH-(Alk) and —SO₂N(Alk)₂,    or A and X may together form a group represented by a formula-   3) n is 0, D is pyrazolyl which may have 1 to 3 substituents    selected from -Alk, -halogeno-lower alkyl, —COOH and —COO-Alk, B is    phenylene or a monocyclic, divalent heteroaromatic ring selected    from the group consisting of thiophene, furan, thiazole, pyridine    and pyrimidine, which may be substituted with Alk, X is —NH—CO—,    —N(OH)—CO—, —CO—NH—, —CH₂—NH— or —CO—N(Alk)-, and A is phenyl which    may have one or more substituents selected from the group consisting    of -Alk, -Hal, —NH₂, —N(Alk)₂, —NO₂, —CN, —OH, —O-Alk and —COO-Alk;    mono-, di- or tricyclic fused heteroaryl selected from the group    consisting of thienyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl,    tetrazolyl, triazolyl, thiadiazolyl, pyridyl, pyrazinyl and    isoquinolyl, which may be substituted with Alk; cycloalkyl; lower    alkenyl which may be substituted with one or more Hal; or Alk, or-   4) X is —NH—CO— or —CO—NH—.

Particularly preferred is a pyrazole derivative or a pharmaceuticallyacceptable salt thereof, in which D is1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl and A is phenyl which may besubstituted with Hal, or D is 3,5-bis(trifluoromethyl)-1H-pyrazol-1-yland A is monocyclic heteroaryl selected from the group consisting ofthiazolyl, thiadiazolyl, thienyl and pyridyl, which may be substitutedwith Alk.

Unless otherwise noted, the term “lower” as used herein means a straightor branched carbon chain having from 1 to 6 carbon atoms. Examples ofpreferred groups include methyl, ethyl, propyl and the like as “loweralkyl (Alk)”, vinyl, 1-propenyl, 1,2-dimethyl-1-propenyl and the like as“lower alkenyl” and ethynyl and the like as “lower alkynyl”. The“halogen atom (Hal)” is I, Br, F or Cl. The “halogeno-lower alkyl” is anAlk substituted with one or more-Hal, and trifluoromethyl isparticularly preferable. The “aryl” is an aryl group having from 6 to 14carbon atoms, preferably phenyl or naphthyl. The “cycloalkyl” is acycloalkyl having from 3 to 8 carbon atoms, preferably cyclopropyl orcyclohexyl.

The “monocyclic, divalent heteroaromatic ring group” is a five- orsix-membered monocyclic, divalent heteroaromatic ring group whichcontains from 1 to 4 hetero-atoms selected from N. S and O atoms, andfuran-2,5-diyl, thiophene-2,5-diyl, thiazole-2,5-diyl, pyridine-2,5-diyland pyrimidine-2,5-diyl are particularly preferable. The “phenylene; ispreferably 1,4-phenylene.

The “mono-, di- or tricyclic fused heteroaryl” is a five- orsix-membered mono-, di- or tricyclic fused ring which contains from 1 to5 of O, S or N atom as heterocyclic atoms. The “nitrogen-containingsaturated ring” is a five- or six-membered nitrogen-containing saturatedring which contains 1 or 2 N atoms as ring atoms and may further containone O or S atom. The “nitrogen-containing, divalent, saturated ringgroup” is preferably piperidine-1,4-diyl. When n is 0, D and B aredirectly bonded.

The compound of this invention may exist in the form of geometricalisomers or tautomers depending on the kinds of substituent groups, andthese isomers in separated forms or mixtures thereof are included in thepresent invention. Also, the compound of the present invention may haveasymmetric carbon atoms, so that it may exist in (R) and (S) opticalisomer forms based on such carbon atoms. All of the mixtures and theisolated forms of these optical isomers are included in the presentinvention.

The compound (I) or (I′) of this invention may form an acid additionsalt or, depending on the kinds of substituent groups, a salt with abase. Such salts are pharmaceutically acceptable ones, and theirpreferred examples include acid addition salts with inorganic acids(e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuricacid, phosphoric acid and the like) or with organic acids (e.g., formicacid, acetic acid, propionic acid, oxalic acid, malonic acid, succinicacid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid,citric acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, aspartic acid, glutamic acid and the like) andsalts with inorganic bases (e.g., sodium, potassium, magnesium, calcium,aluminum and the like) or with organic bases (e.g., methylamine,ethylamine, ethanolamine, lysine, ornithine and the like), as well asammonium salts.

In addition, various hydrates and solvates and polymorphism of thecompound (I) or (I′) and salts thereof are also included in thisinvention.

(Production Method)

The compound of the present invention and a pharmaceutically acceptablesalt thereof can be produced by making use of the features of its basicstructure or the kinds of its substituents and by employing variousknown synthesis methods. In that case, depending on the kind of eachfunctional group, it may sometimes be effective from the viewpoint ofproduction techniques to replace said functional group with anappropriate protecting group, namely a group which can be converted intosaid functional group easily, at the stage of raw materials orintermediates. Thereafter, the compound of interest can be obtained byremoving the protecting group as occasion demands. Examples of suchfunctional groups include a hydroxyl group, a carboxyl group and thelike and examples of their protecting groups include those which aredescribed in “Protective Groups in Organic Synthesis”, 2nd edition,edited by Greene and Wuts, which may be optionally used depending on thereaction conditions.

The following describes typical methods for the preparation of thecompound of the present invention.

In this method, as shown in the above reaction formula, the compound(I-1) or (I-2) of the present invention is obtained by subjecting anamine derivative represented by the general formula (II) or (V) and acarboxylic acid derivative represented by the general formula (III) or(IV) to amidation reaction.

The carboxylic acid derivative (III) or (IV) which can be used in theproduction method 1 is a free carboxylic acid or a reactive derivativethereof, and examples of the reactive derivative include acid halidessuch as acid chlorides, acid bromides and the like; acid azides; activeesters which can be prepared using methanol, ethanol, benzyl alcohol,phenol which may be substituted, 1-hydroxybenzotriazole,N-hydroxysuccinimide and the like; symmetric acid anhydrides; and mixedacid anhydrides with ethoxycarbonyl chloride, isobutylcarbonyl chloride,alkylcarboxylic acid, p-toluenesulfonic acid and the like. Thesereactive derivatives are commercially available or can be produced bythe usual procedures.

The amidating reaction can be carried out by the usual procedures.

When the reaction is carried out using a free carboxylic acid, it isnecessary to use a condensing agent such asN,N′-dicyclohexylcarbodiimide (DCC),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (WSCD) or the like orcarboxylic acid activating agent such as 1,1′ carbonyldiimidazole,N,N′-disuccinimidyl carbonate, diphenylphosphoryl azide, phosphorusoxychloride, phosphorus trichloride,triphenylphosphine/N-bromosuccinimide or the like.

The reaction is carried out using an amine derivative represented by thegeneral formula (II) or (V) and a carboxylic acid derivative representedby the general formula (III) or (IV), in equimolar amounts or one ofthem in excess amount, in a reaction inert organic solvent such aspyridine, tetrahydrofuran (THF), dioxane, ether, benzene, toluene,dichloromethane, 1,2-dichloroethane (DCE), chloroform,N,N-dimethylformamide (DMF), ethyl acetate, acetonitrile or the like.The reaction temperature is optionally selected depending on the kindsof reaction derivatives.

Depending on the kinds of reaction derivatives, addition of a base suchas triethylamine, pyridine, picoline, N,N-dimethylaniline, potassiumcarbonate, sodium hydroxide or the like may be advantageous in somecases from the viewpoint of accelerating the reaction. It is possible touse pyridine also as the solvent.

(In the above reaction formula, each of Ra and Rb represents H or Alk.)

In this production method, the compound (I-3) of the present inventionis obtained by carrying out trifluoroacetylation of the carbon atomadjacent to the ketone of a compound represented by the general formula(VI) and then effecting cyclization by reacting it with a hydrazinederivative.

The first step trifluoroacetylation can be carried out by allowing thecompound to react with a trifluoroacetylation agent (for example, ethyltrifluoroacetate, trifluoroacetic anhydride or the like) at atemperature of from −78° C. to reflux temperature in a solvent such asmethanol, ethanol, 1,3-dimethylimidazolidin-2-one (DMI), THF, DMF or thelike, in the presence of a base such as sodium methoxide, sodiumethoxide, alkali metal hexamethyldisilazide, alkali metal hydride, alkyllithium, triethylamine or the like.

The second step cyclization reaction can be carried out by allowing thecompound obtained in the first step to react with a hydrazine derivativein a solvent such as methanol, ethanol or the like, or without solvent,in the presence or absence of an acid such as acetic acid, hydrochloricacid or the like or Lewis acid such as titanium(IV) isopropoxide,titanium(IV) chloride, boron trifluoride-diethyl ether complex or thelike. This reaction can be carried out at a temperature of from coolingtemperature to reflux temperature.

As shown in the above reaction formula, this production method is amethod in which the compound (I-4) or (I-5) of the invention is obtainedby a reductive amination reaction of an amine derivative represented bythe general formula (II) or (V) with an aldehyde derivative representedby the general formula VII) or (VIII).

This reductive amination reaction is carried out by allowing bothcompounds to react with each other in the same inert solvent of the caseof amidation of the production method 1, and reducing the thus formedSchiff base after its isolation or directly without isolation. It isadvantageous to carry out formation of Schiff base in the presence ofthe aforementioned Lewis acid, p-toluenesulfonic acid, adipic acid,acetic acid, hydrochloric acid or the like acid catalyst, in thepresence of molecular sieves, potassium hydroxide or the likedehydrating agent or by removing formed water using Dean-Stark trap. Thereaction temperature can be optionally set but is preferably from roomtemperature to reflux temperature.

Reduction of the Schiff base can be carried out at a temperature of from−20° C. to heat reflux, by adding a reducing agent such as a metalhydride complex (e.g., sodium cyanoborohydride, sodiumtriacetoxyborohydride or sodium borohydride) or borane. Alternatively,it can be effected by carrying out the reaction using a reductioncatalyst (e.g., palladium-carbon or Raney nickel) at a temperature offrom 0° C. to 100° C. in a hydrogen atmosphere of from ordinary pressureto 50 kg/cm², in a solvent such as methanol, ethanol, ethyl acetate,acetic acid or the like in the presence or absence of an acid such asacetic acid, hydrochloric acid or the like.

A compound of the invention in which X is —SO₂—NR¹— or —NR¹—SO₂— can beproduced in the same manner as the aforementioned production method 1,except that a sulfonic acid derivative is used instead of the carboxylicacid derivative.

A compound in which X is —CR⁴═CR⁵— can be produced by effectingformation of an olefin from an organic phosphorus compound and analdehyde by the Horner-Emmons reaction or Wittig reaction. This reactioncan be carried out at a temperature of from −78° C. to heat reflux inTHF, DMF or the like solvent in the presence of a base such as lithiumdiisopropylamide, sodium hydride, triethylamine, alkyl lithium or phenyllithium.

N-Alkylation of the nitrogen atom of amino group or amido group of X andN-alkylation of the ring nitrogen atoms can be carried out by a usuallyused N-alkylation method, for example, by allowing an amine derivativeto react with an alkyl compound having a usual leaving group such as ahalogen atom or an organic sulfone residue, at a temperature of fromcooling to reflux in DMF, acetone, 2-butanone, acetonitrile or the likeinert solvent or without solvent in the presence or absence of potassiumcarbonate, triethylamine, sodium hydride or the like base.

In addition to be above, introduction of substituents into respectiverings, modification of groups, elimination of protecting groups and thelike techniques can be carried out in the usual-way.

(Production Method of Starting Compounds)

Starting compounds of the aforementioned production methods arecommercially available or can be produced easily by methods well knownto those skilled in the art.

Each of the reaction products obtained by the aforementioned productionmethods is isolated and purified as a free compound, a salt thereof, ahydrate thereof or a solvate thereof. The salt can be produced by ausual salt forming method. The isolation and purification are carriedout by employing usually used chemical techniques such as extraction,concentration, evaporation, crystallization, filtration,recrystallization, various types of chromatography and the like. Variousforms of isomers can be isolated by the usual procedures making use ofphysicochemical differences among isomers. For example, optical isomerscan be separated by means of a conventional racemic resolution methodsuch as fractional crystallization or a chromatography. In addition, anoptical isomer can also be synthesized from an appropriate opticallyactive starting compound.

INDUSTRIAL APPLICABILITY

7 The compound of the present invention is useful as an activeingredient of pharmaceutical compositions. Since it has inhibitoryactivities on CRACC and IL-2 production, it is particularly useful as aninhibitor of CRACC or IL-2 production.

It also is particularly useful as an agent for use in the prevention andtreatment of allergic, inflammatory or autoimmune diseases in whichCRACC and/or IL-2 production are concerned. In this connection, examplesof the allergic, inflammatory or autoimmune diseases include variousdiseases in which CRACC and/or IL-2 production are concerned such asbronchial asthma, psoriasis, atopic diseases including atopicdermatitis, inflammatory bowel diseases including Crohn disease, pepticulcer, glomerular nephritis, hepatitis, pancreatitis, collagen disease,rheumatoid arthritis, osteoarthritis, rejection on transplantation andthe like.

Applicability of the compound of the present invention to theaforementioned diseases is evident from the results of in vitro tests oninhibition of CRACC and IL-2 production, which will be described later,as well as the results of various tests carried out using animal modelsfor diseases such as an antigen-induced airway eosinophilia as a typicalmodel for bronchial asthma, some T-cell-dependent disease models and acollagen-induced arthritis in mice. In addition, since the compounds ofthe present invention also have inhibitory effects on IL-4, IL-5, MMP-1and TNFα production, such results also support its applicability to theaforementioned diseases.

On the other hand, anti-proliferative effect of the CRACC inhibitorsuggests that it should be useful in preventing or treatingproliferative or progressive diseases such as malignant tumor,arteriosclerosis, multiple organ sclerosis, various types of fibrosis,burn keloid and the like. Also, since the CRACC inhibitor inhibitsactivation of inflammatory cells such as mast cells, leukocytes andastrocytes, which concern with inflammation in several peripheral orbrain tissues, its action to protect tissues from their damages such asischemia-reperfusion injury, head injury, cerebral infarction andmyocardial infarction can be expected.

In particular, the compound of the present invention which is possessedof CRACC selective inhibitory activity over VOCC is useful, because itcan cause CRACC inhibition without VOCC activation-induced undesirablereactions in central nerve system and cardiovascular system and thelike.

The following shows certain tests and their results in order to confirmpharmacological actions of the compound of the present invention.

(1) CRACC Inhibitory Activity

Jurkat cells (6×10⁶/ml) suspension loaded with a calcium indicatorfluorescence dye fura-2 (1 μM) was dispensed in 100 μl portions intowells of a 96 well microplate. Intracellular calcium increase stimulatedwith a calcium pump inhibitor (thapsigargin) was induced by adding toeach well a 100 μl of Hanks' balanced salt solution containing a drug tobe tested in two times higher concentration than the final concentrationand 2 μM of thapsigargin (final concentration, 1 μM), and, after 30minutes of the addition, a fluorescence intensity ratio (R) wascalculated from two fluorescence intensities obtained at excitation wavelengths of 340 nm/500 nm and 380 nm/500 nm, respectively. In calculatingR, self-fluorescence of the drug to be tested was measured in acell-free system, and the effect of the self-fluorescence on the fura-2fluorescence was corrected.

The intracellular calcium concentration was obtained by the followingcalculation formula based on a maximum reaction of R (Rmax) obtained by25 μM ionomycin stimulation, a minimum reaction of R (Rmin) obtained by5 μM ionomycin+1 mM EGTA stimulation, a fluorescence efficiency (Sb₂) ofa calcium binding dye at an excitation wave length of 380 nm/500 nm anda fluorescence efficiency (Sf₂) of a calcium dissociation dye at anexcitation wave length of 380 nm/500 nm.

Calculation Formula: Intracellular Calcium Concentration(nM)==224×[(R−Rmin)/(Rmax−R)]×[Sf ₂ /Sb ₂]

Using the thus calculated intracellular calcium concentration in thepresence of a predetermined concentration of each of the drugs and thatof the control solvent, a ratio of inhibiting calcium influx (CRACCinhibition) was obtained to calculate its concentration to inhibit 50%of CRACC (IC₅₀ value).

(2) Selectivity of CRACC Inhibition Against VOCC

A suspension of rat neuroblasts PC12-h5 (2×10⁶/ml) loaded with a calciumindicator fluorescence dye fura-2 (1 μM) was dispensed in 100 μlportions into wells of a 96 well microplate. Intracellular calciumincrease stimulated with high concentration potassium chloride wasinduced by adding to each well a 100 μl of Hanks' balanced salt solutioncontaining a drug to be tested in two times higher concentration thanthe final concentration and 100 mM of KCl (final concentration, 50 mM),and, after 30 minutes of the addition, a fluorescence intensity ratio(R) was calculated from two fluorescence intensities obtained atexcitation wave lengths of 340 nm/500 nm and 380 nm/500 nm,respectively. In calculating R, self-fluorescence of the drug to betested was measured in a cell-free system, and the effect of theself-fluorescence on the fura-2 fluorescence was corrected.

The IC₅₀ value of VOCC inhibition was calculated in the same manner asthe case of the aforementioned CRACC inhibition, and compared with thatof CRACC inhibition.

The CRACC inhibition activity (IC₅₀ value) of the novel compounds ofExamples 1, 5, 32, 36, 38, 50, 53 and 72 and the known compounds A and D(both purchased from MYBRIDGE) was within the range of from 0.51 to0.050 μM. In addition, the CRACC inhibition activity of these compoundswas superior to the VOCC inhibition activity by a factor of from 16 to200, thus showing selectivity.

(3) Inhibitory Effect on IL-2 Production

Inhibitory effect of the invention compound on IL-2 production fromJurkat cells was tested in accordance with the method described by S.Clare Chung et al. in Br. J. Pharmacol., 113: 861-868, 1994, and itsIC₅₀ value was calculated.

Compounds of the Examples 1, 5, 32, 36, 38, 50, 53 and 72 and CompoundsA and D showed IC₅₀ values of 1 μM or less.

(4) Effect on TNCB-Induced Contact Hypersensitivity Model

In five-week-old male ICR mice (SLC), effect of the invention compoundon TNCB-induced contact hypersensitivity was tested in almost the samemanner as the method described in Current Protocols in Immunology (JohnWiley & Sons, Inc., 1994). Compounds of this invention inhibitedTNCB-induced contact hypersensitivity in a dose-dependent manner.

(5) Inhibitory Effect on Concanavalin A (ConA)-Induced Hepatitis in Mice

In four to five-week-old female Balb/c mice (SLC), this test was carriedout by employing a method similar to the method reported by G. Tiegs etal. in J. Clin. Invest., 90: 196-203 (1992). Compounds of this inventioninhibited ConA-induced hepatitis in a dose-dependent manner.

(6) Inhibitory Effect on Collagen-Induced Arthritis in Mice

In five-week-old male DBA/1J mice (Charles River Japan), inhibitoryeffect on arthritis was tested in the similar manner as the methodsreported by Fumio Nishikaku and Yoshihiko Koga in Immunopharmacology,25, 65-74 (1993) and by Fuminori Kato, Masanao Nomura and Kyoko Nakamurain Annals of the Rheumatic Disease, 55, 535-539 (1996). Compounds ofthis invention showed significant inhibition on arthritis.

(7) Inhibitory Effect on Antigen-Induced Airway Eosinophilia in Rat

In four-week-old male BN rats, inhibitory effect on antigen-inducedairway eosinophilia was tested in almost the same manner as the methodreported by W. Elwood et al. in Inflamm. Res., 44: 83-86 (1995). In thisconnection, the drug was administered 30 minutes before the antigenexposure in the case of intravenous injection or 1 hour before and 3hours after the antigen exposure in the case of oral administration.

In this model, compounds of this invention inhibited numbers ofinfiltrated total leukocytes and that of infiltrated eosinophils intoairways.

A pharmaceutical composition which contains the compound (I′) of thepresent invention or a salt thereof and a pharmaceutically acceptablecarrier can be prepared by a usually used method using at least one ofcompounds represented by the general formula (I′) or salts thereof and acarrier for medicinal use, a filler and other additives usually used inpharmaceutical preparations. Its administration may be effected eitherby oral administration in the form of tablets, pills, capsules,granules, powders, solutions and the like or by parenteraladministration in the form of intravenous, intramuscular and the likeinjections, suppositories, percutaneous absorption preparations and thelike.

The solid composition for use in the oral administration according tothe present invention is used in the form of tablets, powders, granulesand the like. In such a solid composition, one or more active substancesare mixed with at least one inert diluent such as lactose, mannitol,glucose, hydroxypropylcellulose, microcrystalline cellulose, starch,polyvinyl pyrrolidone or aluminum magnesium silicate. By the usualprocedures, the composition may contain other additives than the inertdiluent, such as a lubricant (e.g., magnesium-stearate or the like), adisintegrating agent (e.g., calcium cellulose glycolate or the like), astabilizing agent (e.g., lactose or the like) and a solubilizationassisting agent (e.g., glutamic acid, aspartic acid or the like). Ifnecessary, tablets or pills may be coated with films of a sugar or agastric or enteric substance such as sucrose, gelatin,hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate or thelike.

The liquid composition for oral administration use includespharmaceutically acceptable emulsions, solutions, suspensions, syrups,elixirs and the like and contains a generally used inert diluent such aspurified water or ethanol. In addition to the inert diluent, thiscomposition may also contain auxiliary agents such as a moisteningagent, a suspending agent and the like, as well as sweeteners, flavors,aromatics and antiseptics.

The injections for parenteral administration use include aseptic aqueousor non-aqueous solutions, suspensions and emulsions. Examples of thediluent for use in the aqueous solutions and suspensions includedistilled water for injection use and physiological saline. Examples ofthe diluent for use in the non-aqueous solutions and suspensions includepropylene glycol, polyethylene glycol, plant oil (e.g., olive oil or thelike), alcohol (e.g., ethanol and the like), and polysorbate 80. Such acomposition may further contain auxiliary agents such as an antiseptic,a moistening agent, an emulsifying agent, a dispersing agent, astabilizing agent (lactose for example) and a solubilization assistingagent (glutamic acid or aspartic acid for example). These compositionsare sterilized by filtration through a bacteria retaining filter,blending of a germicide or irradiation. Alternatively, they may be usedby firstly making into sterile solid compositions and then dissolvingthem in sterile water or a sterile solvent for injection use prior totheir use.

In the case of oral administration, suitable daily dose is usually fromabout 0.001 to 10 mg/kg body weight, and the daily dose is administeredonce a day or divided into 2 to 4 doses per day. In the case ofintravenous injection, suitable daily dose is usually from about 0.0001to 1 mg/kg body weight, and the daily dose is administered once perseveral days, or once a day or divided into a plurality of doses perday. The dose is optionally decided by taking into considerationsymptoms, age, sex and the like of each patient to be treated.

BEST MODE FOR CARRYING OUT THE INVENTION

The following describes the present invention further in detail based onExamples. Compounds of the present invention are not limited to thecompounds described in the following Examples. In this connection,methods for the production of the starting material compounds to be usedin the Examples are described as Reference Examples.

REFERENCE EXAMPLE 1

Sodium methoxide was added to a mixture of 2-acetylthiazole and methanolunder ice-cooling, followed by stirring at room temperature for 20minutes. Ethyl trifluoroacetate was added to the reaction solution underice-cooling. After stirring for 19 hours while heating under reflux, itwas purified in the usual way. Then, methyl hydrazine, acetic acid andethanol were added thereto. After stirring for 30 minutes while heatingunder reflux, it was subjected to purification in the usual way to give2-(1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl)thiazole.

REFERENCE EXAMPLE 2

An n-butyl lithium-n-hexane solution (1.6 M) was added to a mixture ofdiisopropylamine and THF at −30° C. or below, followed by stirring at−30 to −50° C. for 15 minutes. Then, 2-propionylthiophene was added tothe reaction solution at −60° C. or below, followed by stirring at −60°C. or below for 90 minutes. The reaction solution was added to a mixtureof trifluoroacetic anhydride and THF, which was cooled at −60° C. Afterstirring at −60° C. for 1 hour, it was subjected to purification in theusual way to give a brown oil. Hydrazine hydrochloride and ethanol wereadded to this brown oil. After stirring at 50° C. for 2 hours, it wassubjected to purification in the usual way to give4-methyl-3-(2-thienyl)-5-trifluoromethyl-1H-pyrazole as a brown solid.

REFERENCE EXAMPLE 3

An n-butyl lithium-n-hexane solution (1.6 M) was added to a mixture of3-(2-thienyl)-5-trifluoromethyl-1H-pyrazole and THF at −60° C. or below,followed by stirring at 0° C. for 50 minutes. Ethyl chloroformate wasadded to the reaction solution at −60° C. or below. After stirring at−78° C. for 1 hour, it was subjected to purification in the usual way togive a mixture of ethyl5-(1-ethoxycarbonyl-5-trifluoromethyl-1H-pyrazol-3-yl)thiophene-2-carboxylateand ethyl5-(1-ethoxycarbonyl-3-trifluoromethyl-1H-pyrazol-5-yl)thiophene-2-carboxylateas a light yellow solid. Then, a mixture of this mixture with sodiumbicarbonate, ethanol, 1,4-dioxane and water was stirred at roomtemperature for 3 days, and it was subjected to purification in theusual way to give ethyl5-(5-trifluoromethyl-1H-pyrazol-3-yl)thiophene-2-carboxylate ascolorless powder crystals. This was hydrolyzed with a base in the usualway to give 5-(5-trifluoromethyl-1H-pyrazol-3-yl)thiophene-2-carboxylicacid.

REFERENCE EXAMPLE 4

An n-butyl lithium-n-hexane solution (1.6 M) was added to a mixture of2-(1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl)thiazole and THF at −50°C. or below, followed by stirring at −50° C. or below for 90 minutes.Ethyl chloroformate was added to the reaction solution at −20° C. orbelow. After stirring at −20° C. or below for 15 minutes, it wassubjected to purification in the usual way to give ethyl2-(1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl)thiazole-5-carboxylate.This was hydrolyzed with a base in the usual way to give2-(1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl)thiazole-5-carboxylicacid.

REFERENCE EXAMPLE 5

A mixture of ethyl5-(5-trifluoromethyl-1H-pyrazol-3-yl)thiophene-2-carboxylate, ethyliodide, potassium carbonate and DMF was stirred at room temperature for9 hours. The residue obtained by a usual treatment was eluted by silicagel chromatography (eluent; n-hexane:ethyl acetate=15:1) to give ethyl5-(1-ethyl-5-trifluoromethyl-1H-pyrazol-3-yl)thiophene-2-carboxylate ascolorless needle crystals. Also, by changing the eluent of the silicagel chromatography to n-hexane:ethyl acetate=10:1, ethyl5-(1-ethyl-3-trifluoromethyl-1H-pyrazol-5-yl)thiophene-2-carboxylate wasobtained as a light yellow oil. By hydrolyzing these compounds with abase in the usual way, a)5-(1-ethyl-5-trifluoromethyl-1H-pyrazol-3-yl)thiophene-2-carboxylic acidand b)5-(1-ethyl-3-trifluoromethyl-1H-pyrazol-5-yl)thiophene-2-carboxylic acidwere obtained.

REFERENCE EXAMPLE 6

a)5-(1-Isopropyl-5-trifluoromethyl-1H-pyrazol-3-yl)thiophene-2-carboxylicacid and b)5-(1-isopropyl-3-trifluoromethyl-1H-pyrazol-5-yl)thiophene-2-carboxylicacid were obtained in the same manner as described in Reference Example5.

REFERENCE EXAMPLE 7

4-Methyl-3-(2-thienyl)-5-trifluoromethyl-1H-pyrazole was allowed toreact with an n-butyl lithium -n-hexane solution (1.6 M). Further, ethylchloroformate was added at −50° C. or below. After stirring at −50° C.or below for 30 minutes, it was subjected to purification in the usualway to give a yellow oil. By hydrolyzing this in the usual way,5-(4-methyl-5-trifluoromethyl-1H-pyrazol-3-yl)thiophene-2-carboxylicacid was obtained as colorless powder crystals.

REFERENCE EXAMPLE 8

A mixture of5-(1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl)thiophene-2-carboxylicacid, oxalyl chloride, DMF and DCE was stirred at room temperature for90 minutes and then treated in the usual way to give5-(1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl)thiophene-2-carbonylchloride as a brown solid.

REFERENCE EXAMPLE 9

A mixture of5-(1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl)thiophene-2-carboxylicacid, diphenylphosphoryl azide, triethylamine and toluene was stirred at50° C. for 30 minutes. Then, tert-butanol was added to the reactionsolution. After stirring at 80° C. for 5 hours, it was subjected topurification in the usual way to give tert-butyl5-(1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl)thiophene-2-carbamate aslight yellow crystals.

REFERENCE EXAMPLE 10

A mixture of tert-butyl5-(1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl)thiophene-2-carbamate,trifluoroacetic acid and dichloromethane was stirred at room temperaturefor 2 days and then subjected to purification and salt formation in theusual way to give5-(5-amino-2-thienyl)-1-methyl-3-trifluoromethyl-1H-pyrazolehydrochloride as light yellow powder crystals.

REFERENCE EXAMPLE 11

Zinc powder and ammonium chloride were added to an aqueous ethanolsolution of 1-(4-nitrophenyl)-3,5-bis(trifluoromethyl)-1H-pyrazole underice-cooling, followed by stirring at 20° C. or below for 30 minutes. Theinsoluble matter in the reaction solution was removed by celitefiltration, and then the filtrate was treated in the usual way to give1-(4-hydroxyaminophenyl)-3,5-bis(trifluoromethyl)-1H-pyrazole as acolorless solid.

REFERENCE EXAMPLE 12

A mixture of 5 N sodium hydroxide aqueous solution and ethanol was addedto a mixture of5-(1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl)thiophene-2-carboxyaldehyde, silver nitrate powder and ethanol under ice-cooling. Afterstirring at room temperature for 1 hour, it was subjected topurification in the usual way to give5-(1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl)thiophene-2-carboxylicacid as colorless powder.

EXAMPLE 1

A mixture of 4-methylthiazole-5-carboxylic acid (108 mg),4-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]aniline (223 mg), WSCDhydrochloride (152 mg) and DCE (5 ml) was stirred overnight at roomtemperature. Water (10 ml) was added to the reaction mixture, and thethus formed product was extracted with a mixed solvent of diethyl ether(5 ml) and ethyl acetate (10 ml). The extract was washed with 1 Nhydrochloric acid, saturated sodium hydrogencarbonate aqueous solutionand saturated brine in that order. The resulting organic layer was driedover anhydrous magnesium sulfate and then concentrated under a reducedpressure. The thus obtained residue was purified by silica gel columnchromatography (eluent; n-hexane:ethyl acetate=3:1-2:1) and thenrecrystallized from a mixed solvent of ethyl acetate and n-hexane togive4-methyl-4′-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]thiazole-5-carboxyanilide(143 mg) as colorless needles.

EXAMPLE 2

4-Chlorobenzoyl chloride (88 mg) and THF (2 ml) were added to a mixtureof 4-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]aniline (150 mg),triethylamine (57 mg) and THF (2 ml) under ice-cooling, followed bystirring at room temperature for 4 hours. Water was added to thereaction solution, the thus formed product was extracted with ethylacetate and then the extract was washed with 1-N-hydrochloric acidaqueous solution, saturated sodium bicarbonate aqueous solution andsaturated brine in that order. The organic layer was dried overanhydrous magnesium sulfate and then concentrated under a reducedpressure. By recrystallizing the resulting residue from a mixed solventof ethyl acetate and n-hexane,4-chloro-4′-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]benzanilide (105mg) was obtained as colorless powder crystals.

EXAMPLE 3

A mixture of4′-chloro-5-(4-methyl-5-trifluoromethyl-1H-pyrazol-3-yl)thiophene-2-carboxyanilide(360 mg), methyl iodide (199 mg), potassium carbonate (129 mg) and DMF(5 ml) was stirred at room temperature for 3 days. Water (10 ml) wasadded to the reaction solution, the thus formed product was extractedwith ethyl acetate and then the extract was washed with saturated brine.The organic layer was dried over anhydrous magnesium sulfate and thenconcentrated under a reduced pressure. The resulting residue waspurified by silica gel column chromatography (eluent; n-hexane:ethylacetate=9:1-4:1) and then recrystallized from a mixed solvent of ethylacetate and n-hexane to give4′-chloro-5-(1,4-dimethyl-5-trifluoromethyl-1H-pyrazol-3-yl)thiophene-2-carboxyanilide(13 mg) as colorless powder crystals.

EXAMPLE 4

In the silica gel column chromatography treatment of Example 3, acompound eluted after the compound of Example 3 was recrystallized froma mixed solvent of ethyl acetate and hexane to give4′-chloro-5-(1,4-dimethyl-3-trifluoromethyl-1H-pyrazol-5-yl)thiophene-2-carboxyanilide(86 mg) as colorless powder crystals.

EXAMPLE 5

A mixture of5-(1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl)thiophene-2-carbonylchloride (150 mg) and dichloromethane (1.5 ml) was added underice-cooling to a mixture of 2-chloroaniline (68 mg), pyridine (42 mg)and dichloromethane (2 ml), followed by stirring for 30 minutes at roomtemperature. Saturated sodium hydrogencarbonate aqueous solution wasadded to the reaction mixture, the thus formed product was extractedwith ethyl acetate and then the extract was washed with saturated brine.The resulting organic layer was dried over anhydrous magnesium sulfateand then concentrated under a reduced pressure. The resulting residuewas recrystallized from ethanol to give2′-chloro-5-(1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl)thiophene-2-carboxyanilide(80 mg) as colorless crystals.

EXAMPLE 6

5-(1-Methyl-3-trifluoromethyl-1H-pyrazol-5-yl)thiophene-2-carbonylchloride (295 mg) and THF (3 ml) were added to a mixture of2-amino-1-methylpyrrole hydrochloride (202 mg), potassium carbonate (553mg), THF (2 ml) and water (4 ml), followed by stirring at roomtemperature for 30 minutes. Water was added to the reaction solution,the thus formed product was extracted with ethyl acetate and then theextract was washed with 1 N hydrochloric acid, saturated sodiumbicarbonate aqueous solution and water in that order. The organic layerwas dried over anhydrous magnesium sulfate and then concentrated under areduced pressure. The resulting residue was purified by silica gelcolumn chromatography (eluent; n-hexane:ethyl acetate=2:1-3:2) and thenrecrystallized from a mixed solvent of ethyl acetate and n-hexane togiveN-(1-methyl-2-pyrrolyl)-5-(1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl)thiophene-2-carboxamide(126 mg) as light yellow powder crystals.

EXAMPLE 7

5-(1-Methyl-3-trifluoromethyl-1H-pyrazol-5-yl)thiophene-2-carbonylchloride (150 mg) and THF (2 ml) were added to a mixture of 70%ethylamine aqueous solution (1 ml) and THF (2 ml), followed by stirringat room temperature for 2 hours. Water was added to the reactionsolution, the thus formed product was extracted with ethyl acetate andthen the extract was washed with saturated brine. The organic layer wasdried over anhydrous magnesium sulfate and then concentrated under areduced pressure. The resulting residue was recrystallized from a mixedsolvent of ethyl acetate and n-hexane to giveN-ethyl-S-(1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl)thiophene-2-carboxamide(96 mg) as colorless powder crystals.

EXAMPLE 8

5-(1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl)thiophene-2-carbonylchloride (100 mg) and dichloromethane (2 ml) were added to a mixture of2-aminothiazole (68 mg), saturated sodium bicarbonate aqueous solution(1 ml) and dichloromethane (1 ml), followed by stirring at roomtemperature for 5 hours. Water was added to the reaction solution, thethus formed product was extracted with ethyl acetate and then theextract was washed with saturated brine. The organic layer was driedover anhydrous magnesium sulfate and then concentrated under a reducedpressure. The resulting residue was purified by silica gelcolumn-chromatography (eluent; n-hexane:ethyl acetate=4:1-2:1) and thenwashed with diethyl ether to give5-(1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl)-N-(2-thiazolyl)thiophene-2-carboxamide(68 mg) as colorless solid.

EXAMPLE 9

Sodium methoxide (257 mg) was added to a mixture of3′-acetyl-4-chlorobenzanilide (1.00 g) and methanol (10 ml) underice-cooling, followed by stirring at room temperature for 2 hours. Ethyltrifluoroacetate (0.522 ml) was added to the reaction solution underice-cooling, followed by stirring under heat reflux for 3 days. Water(50 ml) was added to the reaction mixture, the thus formed product wasextracted with ethyl acetate and then the extract was washed withsaturated brine. The organic layer was dried over anhydrous sodiumsulfate and then concentrated under a reduced pressure. The resultingresidue was purified by silica gel column chromatography (eluent;n-hexane:ethyl acetate=2:1-1:1) to give a light yellow oil. A mixture ofthis oil with methyl hydrazine (0.122 ml), acetic acid (1 ml) andethanol (10 ml) was stirred under heat reflux for 15 hours. Afterspontaneous cooling, the reaction solution was concentrated under areduced pressure. After adding ethyl acetate, the thus obtained residuewas washed with saturated sodium bicarbonate aqueous solution andsaturated brine in that order. The organic layer was dried overanhydrous sodium sulfate and then concentrated under a reduced pressure.The resulting residue was purified by silica gel column chromatography(eluent; n-hexane:ethyl acetate=6:1) and then recrystallized from amixed solvent of ethyl acetate and n-hexane to give4-chloro-3′-(1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl)benzanilide (60mg) as colorless powder crystals.

EXAMPLE 10

In the silica gel column chromatography treatment of Example 9, acompound eluted after the compound of Example 9 was recrystallized froma mixed solvent of ethyl acetate and hexane to give4-chloro-3′-(1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl)benzanilide (134mg) as colorless powder crystals.

EXAMPLE 11

Sodium triacetoxyborohydride (530 mg) was added to a mixture of5-(1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl)thiophene-2-carboxyaldehyde (260 mg), 4-chloroaniline (134 mg), acetic acid (0.1 ml) anddichloromethane (3 ml), followed by stirring at room temperature for 2hours and 20 minutes. Saturated sodium bicarbonate aqueous solution (10ml) was added to the reaction solution, the thus formed product wasextracted with ethyl acetate and then the extract was washed withsaturated brine. The organic layer was dried over anhydrous magnesiumsulfate and then concentrated under a reduced pressure. The resultingresidue was purified by silica gel column chromatography (eluent;n-hexane:ethyl acetate=10:1-6:1) to give3-[5-[(4-chloroanilino)methyl]-2-thienyl]-1-methyl-5-trifluoromethyl-1H-pyrazole(313 mg) as a colorless solid.

EXAMPLE 12

A mixture of ethyl1-[4-(4-chlorobenzoylamino)phenyl]-5-trifluoromethyl-4H-pyrazole-4-carboxylate(150 mg), 1 N sodium hydroxide aqueous solution (1 ml) and ethanol (2ml) was stirred at 45° C. for 4 hours. After spontaneous cooling, 1 Nhydrochloric acid aqueous solution (2 ml) was added to the reactionsolution, the thus formed product was extracted with ethyl acetate andthen the extract was washed with saturated brine. The organic layer wasdried over anhydrous magnesium sulfate and then concentrated under areduced pressure. The resulting residue was recrystallized from ethanolto give1-[4-(4-chlorobenzoylamino)phenyl]-5-trifluoromethyl-1H-pyrazole-4-carboxylicacid (91 mg) as colorless powder crystals.

EXAMPLE 13

A mixture of 1-tert-butoxycarbonylpiperidine-4-carboxylic acid (198 mg),4-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl)aniline (206 mg), WSCDhydrochloride (172 mg) and THF (3 ml) was stirred overnight at roomtemperature. After adding ethyl acetate, the reaction solution waswashed with water, saturated sodium bicarbonate aqueous solution, 1 Nhydrochloric acid and saturated brine in that order. The organic layerwas dried over anhydrous sodium sulfate and then concentrated under areduced pressure. The resulting residue was purified by silica gelcolumn chromatography (eluent; n-hexane:ethyl acetate=7:1-5:1) to givetert-butyl4-[4-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]phenylaminocarbonyl]piperidine-1-carboxylate(279 mg) as a colorless amorphous solid. 4 N Hydrochloric acid ethylacetate solution (2.60 ml) was added to a mixture of this solid (263 mg)and ethyl acetate (2.6 ml), followed by stirring at room temperature for2 hours and 45 minutes. The reaction solution was concentrated under areduced pressure, diethyl ether was added to the thus obtained residue,and the mixture was concentrated under a reduced pressure. Byrecrystallizing the resulting residue from a mixed solvent of ethylacetate and n-hexane,(4′-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]piperidine-4-carboxyanilidehydrochloride (201 mg) was obtained as colorless powder crystals.

EXAMPLE 14

Methanesulfonyl chloride (80 mg) was added to a mixture of ethyl1-(4-aminophenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylate (150 mg),triethylamine (76 mg) and THF (2 ml) under ice-cooling, followed bystirring at room temperature for 4 hours. Thereafter, the same treatmentof Example 2 was carried out to give ethyl1-(4-methanesulfonylaminophenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylate(29 mg) as a colorless solid.

EXAMPLE 15

To a mixture of5-(1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl)thiophene-2-carboxyaldehyde (583 mg), diethyl 4-chloro-α-fluorobenzylphosphonate (755 mg)and THF (8 ml) was added at −60° C. lithium diisopropylamide preparedfrom diisopropylamine (259 mg) and an n-butyl lithium-n-hexane solution(1.6 N, 1.6 ml), followed by stirring for 6 hours and 30 minutes whilegradually warming it to room temperature. Water (10 ml) was added to thereaction solution, the thus formed product was extracted with ethylacetate and then the extract was washed with saturated brine. Theorganic layer was dried over anhydrous magnesium sulfate and thenconcentrated under a reduced pressure. The resulting residue waspurified by silica gel column chromatography (eluent; n-hexane:ethylacetate=16:1-8:1) to give5-[5-[(E)-2-(4-chlorophenyl)-2-fluorovinyl]-2-thienyl]-1-methyl-3-trifluoromethyl-1H-pyrazole(32 mg) as an yellow oil.

EXAMPLE 16

4-Chlorophenyl isocyanate (461 mg) was added to a mixture of4-(1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl)piperidine (540 mg) andTHF (5 ml) under ice-cooling, followed by stirring overnight at roomtemperature. Water (10 ml) was added to the reaction solution, the thusformed product was extracted with ethyl acetate and then the extract waswashed with saturated brine. The organic layer was dried over anhydrousmagnesium sulfate and then concentrated under a reduced pressure. Amixed solvent of acetone and diethyl ether was added to the thusobtained residue, the insoluble matter was removed by filtration andthen the filtrate was concentrated under a reduced pressure. Theresulting residue was purified by silica gel column chromatography(eluent; n-hexane:ethyl acetate=1:1) and then recrystallized from amixed solvent of ethyl acetate and n-hexane to give4′-chloro-4-(1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl)piperidine-1-carboxyanilide(391 mg) as colorless powder crystals.

EXAMPLE 17

A mixture of 1-trityl-1H-imidazole-4-carboxylic acid (300 mg),4-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl)aniline (200 mg), WSCDhydrochloride (162 mg), DMF (0.5 ml) and THF (4 ml) was stirredovernight at room temperature. Water (10 ml) was added to the reactionsolution, the thus formed product was extracted with ethyl acetate andthen the extract was washed with saturated brine. The organic layer wasdried over anhydrous magnesium sulfate and then concentrated under areduced pressure. The resulting residue was purified by silica gelcolumn chromatography (eluent; n-hexane:ethyl acetate=3:1). Then,concentrated-hydrochloric acid (0.1 ml) and acetone (3 ml) were added,followed by stirring overnight at room temperature. The reactionsolution was concentrated under a reduced pressure, diethyl ether wasadded to the thus obtained residue, and then the mixture wasconcentrated under a reduced pressure. A mixed solvent of ethanol anddiethyl ether was added to the thus obtained residue, the insolublematter was removed by filtration and then the filtrate was concentratedunder a reduced pressure. The resulting residue was purified by silicagel column chromatography (eluent; n-hexane:ethyl acetate=1:1-2:3) andthen recrystallized from a mixed solvent of ethyl acetate and n-hexane,thereby obtaining[4′-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]-1H-imidazole-4-carboxyanilide(35 mg) as colorless powder crystals.

Other compounds of Examples shown in the following Tables 2 and 3 wereobtained in the same manner as described in the aforementioned Examples.Structural formulae and physicochemical properties of the compounds ofreference examples are shown in the following Table 1, and structuralformulae and physicochemical properties of the compounds of Examples areshown in Tables 2 and 3. In this connection, compounds having thechemical structures shown, in Tables 4 and 5 can be produced easily inalmost the same manner as the methods described in the aforementionedExamples or production methods, or by applying thereto slightmodifications self-evident to those skilled in the art.

Abbreviations in the tables are Rex: Reference Example; Ex: Example; Co:compound number; Sy: production method (each numeral shows correspondingnumber of the aforementioned Example, indicating that the compound wasproduced by the same manner of the aforementioned Example); Str:structural formula; Dat: physicochemical properties (F: FAB-MS (M+H)⁺;FN: FAB-MS (M−H)⁻; E: EI-MS; M: melting point [° C.]; (d):decomposition; N1: characteristic peak δ ppm of NMR (DMSO-d₆, TMSinternal standard); N2: characteristic peak δ ppm of NMR (CDCl₃, TMSinternal standard); and *: absence of the group. TABLE 1 Rfx Str Dat  1

N2: 4.32(3H, s), 6.90(1H, s), 7.45(1H, d, J = 3.3 Hz), 7.93(1H, d, J =3.0 Hz)  2

N2: 2.29(3H, s), 7.16(1H, dd, J = 5.2, 3.7 Hz), 7.25(1H, dd, J = 4.0,1.0 Hz), 7.44(1H, dd, J = 5.4, 1.0 Hz), 10.86(1H, brs)  3

N1: 7.07(1H, s), 7.60(1H, d, J = 3.7 Hz), 7.76(1H, d, J = 3.7 Hz),14.42(1H, brs)  4

N1: 4.26(3H, s), 7.56(1H, s), 8.52(1H, s)  5a)

N1: 1.42(3H, t, J = 7.1 Hz), 4.30(2H, q, J = 7.2 Hz), 7.46(1 H, s),7.58(1H, d, J = 3.9 Hz), 7.71(1H, d, J = 3.6 Hz), 13.18(1H, brs)  5b)

N1: 1.39(3H, t, J = 7.2 Hz), 4.37(2H, q, J = 7.2 Hz), 7.15(1 H, s),7.53(1H, d, J = 3.9 Hz), 7.80(1H, d, J = 3.9 Hz), 13.46(1H, brs)  6a)

N1: 1.49(6H, d, J = 6.8 Hz), 4.57-4.68(1H, m), 7.32(1H, s), 7.47(1H, d,J = 3.9 Hz), 7.50(1H, d, J = 3.9 Hz)  6b)

N1: 1.44(6H, d, J = 6.9 Hz), 4.77-4.88(1H, m), 7.08(1H, s), 7.48(1H, d,J = 3.9 Hz), 7.80(1H, d, J = 3.6 Hz)  7

N1: 2.28(3H, s), 7.53(1H, d, J = 3.9 Hz), 7.81(1H, d, J = 3.9 Hz),13.53(1H, brs), 14.11(1H, brs)  8

N2: 4.09(3H, s), 6.78(1H, s), 7.30(1H, d, J = 4.4 Hz), 8.00(1H, d, J =3.9 Hz)  9

N2: 1.54-1.56(9H + H₂O, m), 4.00(3H, 6.50(1H, d, J = 3.6 Hz), 6.57(1H,s), 6.91(1H, d, J = 3.9 Hz) 10

N1: 3.96(3H, s), 6.29(1H, d, J = 3.9 Hz), 6.77(1H, s), 7.09(1H, d, J =3.9 Hz), 7.1 (br) 11

F:312 12

F:277

TABLE 2 (Ia)

Ex Re Rf Rg n X A Sy Dat 1 CF₃ H CF₃ 0

NHCO

— M:144-145; N1:2.64(3 H, s) 2 CF₃ H CF₃ 0

NHCO

— M:196-197; N1:7.82(1 H, s) 12 H COOH CF₃ 0

NHCO

— M:>300 13 CF₃ H CF₃ 0

NHCO

— F:407 14 H COOEt CF₃ 0

NHSO₂ Me — M:156-158 17 CF₃ H CF₃ 0

NHCO

— N1:10.23(1H, s) 18 CF₃ H CF₃ 0

NHCO

1 M:183-185_; N1:7.82(1 H, s) 19 CF₃ H CF₃ 0

NHCO

1 M:174-175; N1:8.15 (1 H, d, J = 2.9 Hz), 8.19(1 H, d, J = 3.4 Hz) 20CF₃ H CF₃ 0

N(OH)—CO

1 M:126-129; N2:2.94 H, s), 7.10(1H, s) 21 CF₃ H CF₃ 0

NHCO

1 M:166-168; N1:2.84 (3 H, s), 7.83(1H, s) 22 Me H Me 0

NHCO

1 M:101-103 23 H H H 0

NHCO

1 M:184-186 24 H COOEt CF₃ 0

NHCO

8 M:201-202 25 CF₃ H CF₃ 0

NHCO

1 M:158-159 26 H COOEt CF₃ 0

NHCO

1 M:118-120 27 CF₃ H H 0

NHCO

1 M:158-161 28 CF₃ H CF₃ 0

NHCO

1 M:194-196 29 H H CF₃ 0

NHCO

1 M:133-135 30 CF₃ H CF₃ 0

NHCO

1 M:215-218 31 CF₃ H CF₃ 0

NHCO

1 M:135-136 32 CF₃ H CF₃ 0

NHCO

1 M:169-172; N1:248(3H, s) 33 CF₃ H CF₃ 1

NHCO

1 M:125-126 34 H COOEt CF₃ 0

NHCO

1 M:163-165 35 H COOEt CF₃ 0

NHCO

2 M:141-143 36 CF₃ H CF₃ 0

NHCO

1 M:188-190; N1:9.14(1H, d, J = 1.5 Hz) 37 CF₃ H CF₃ 0

NHCO

1 M:188-190 38 CF₃ H CF₃ 0

NHCO

1 M:156; N1:3.90(3H, s) 39 CF₃ H CF₃ 0

NHCO

1 F:422 40 CF₃ H CF₃ 0

NHCO

1 M:99-100 41 H COOEt CF₃ 0

NHCO

5 M:176-178

TABLE 3 (Ib)

Ex Ra Rb Rc Rd n B X A sy Dat 3 * Me CF₃ Me 0

CONH

— M:210-213 4 Me * CF₃ Me 0

CONH

— M:192-196; N1:2.15(3H, s), 3.91(3H, s) 5 Me * CF₃ H 0

CONH

— M:156; N2: 4.08(3H, s), 7.13(1H, dt, J = 7.8, 15 Hz) 6 Me * CF₃ H 0

CONH

— M:158-159; N1:3.44(3H, s), .4.07(3H, s) 7 Me * CF₃ H 0

CONH Et — M:136-137 8 * Me CF₃ H 0

CONH

— M:244-246; N2:4.04(3H, s) 9 * Me CF₃ H 0

NHCO

— M:173-175; N2:4.02(3H, s) 10 Me * CF₃ H 0

NHCO

— M:150-153 11 * Me CF₃ H 0

CH₂NH

— M:113-115; N2:4.48(2H, s) 15 Me * CF₃ H 0

CH═CF (cis)

— E:386 16 Me * CF₃ H 0

CONH

— M:163-165 42 * H CF₃ H 0

CONH

1 M:246-247 43 Et * CF₃ H 0

CONH

1 M:177; N1: 1.51(3H, t, J = 7.3 Hz), 4.36(2H, q, J = 7.3 Hz) 44 * iPrCF₃ H 0

CONH

1 M188-190; N1:4.59-4.70(1H, m) 45 Me * CF₃ H 0

CONH

1 M:204-206; N1:4.07(3H, s) 46 Me * CF₃ H 0

CONH

1 M:183-185; N2:4.13(3H, s), 6.78(1H, d, J = 4.0 Hz) 47 Me * CF₃ H 0

CONH

2 M:163-164 48 Me * CF₃ H 0

CONH

8 M:247(d) 49 Me * CF₃ H 0

CONH

1 M:185-186; N1:9.32(1H, s), 10.17(1H, s) 50 Me * CF₃ H 0

CONH

2 M:159-161; N2:4.06(3H, s) 51 Me * CF₃ H 0

CONH

2 M:181-183; N2:4.08(3H, s) 52 Me * CF₃ H 0

CONH

2 M:147-148; N1:4.08(3H, s) 53 Me * CF₃ H 0

CONH

5 M:129-130; N2:4.07(3H, s) 54 Me * CF₃ H 0

CONH

8 M:189-192; N2:4.07(3H, s) 55 Me * CF₃ H 0

CONH

8 M:191-192; N2:4.07(3H, s) 56 Me * CF₃ H 0

CONH

2 M:285-287(d) 57 Me * CF₃ H 0

CONH

2 N2:4.07(3H, s) 58 Me * CF₃ H 0

CONH

2 M:166-168; N2:7.13(1H, dd, J = 4.9, 1.5 Hz), 7.31(1H, dd, J = 5.2, 3.2Hz), 7.68(1H, dd, J = 3.0, 1.5 Hz) 59 Me * CF₃ H 0

CONH

5 M:207-210 60 Me * CF₃ H 0

CONH

8 M:140-141; N1:1.10-1.20(1H, m), 1.24-1.37(4H, m), 1.69-1.89(4H, m)61 * Me CF₃ H 0

CONH

1 M:156-157 62 * Me CF₃ H 0

CONH

1 M:197-199 63 * Me CF₃ H 0

CONH

5 M:205-207 64 * Me CF₃ H 0

CONH

5 M:234-236; N2:4.04(3H, m) 65 * Me CF₃ H 0

CONH

8 M:230 66 * Me CF₃ H 0

CONH

1 M:195-196 67 * Me CF₃ H 0

CONH

8 M:211-215 68 Me * CF₃ H 0

NHCO

1 M:148-149; N1:2.86(3H, s) 69 Me * CF₃ H 0

CONMe

5 M:136-137; N1:3.35(3H, s) 70 * Me CF₃ H 0

NHCO

8 M:197-199 71 Me * CF₃ H 0

NHCO

8 M:166-168; N1:11.92(1H, s) 72 Me * CF₃ H 0

NHCO

9 M:187-188; N2:3.93(3H, s) 73 Me * CF₃ H 0

NHCO

9 F:368; N1:2.83(3H, s) 74 Me * CF₃ H 0

CONH

13  M:265-266 75 Me * CF₃ H 0

CONH

1 M:198-200 76 Me * CF₃ H 0

CONH

1 M:206-208 77 Me * CF₃ H 0

CONH

1 M:162-164 78 Me * CF₃ H 0

CONH

8 M:163-164 79 Me * CF₃ H 0

CONH

8 M:211-214 80 Me * CF₃ H 0

CONH

8 M:181-183 81 Me * CF₃ H 0

CONH

5 M:166-167 82 Me * CF₃ H 0

CONH

5 M:183-185 83 Me * CF₃ H 1

CONH

1 M:137-139 84 Me * CF₃ H 0

2 M:153-155

TABLE 4 (Ia)

Co Re Rf Rf n B X A 11 CF₃ H CF₃ 0

NHCO

12 CF₃ H CF₃ 0 NHCO

13 CF₃ H CF₃ 0

NHCO

14 CF₃ H CF₃ 0 NHCS

15 CF₃ H CF₃ 0 NHCS

16 CF₃ H CF₃ 0 NHCS

17 CF₂CF₃ H CF₂CF₃ 0 NHCO

18 CF₂CF₃ H CF₂CF₃ 0 NHCO

TABLE 5 (Ib)

Co Ra Rb Rc Rd n X A 1 * Me CF₃ H 0

CONH

2 Me * CF₃ H 0 CONH 3 * Me CF₃ H 0 CONH

4 Me * CF₃ H 0 CONH 5 * Me CF₃ H 0 CONH

6 Me * CF₃ H 0 CONH 7 Me * CF₂CF₃ H 0 CONH 8 * Me CF₃ H 0

CONH 9 Me * CF₃ H 0 CONH 10 * Me CF₃ H 0

CONH

1-19. (canceled)
 20. A pyrazole compound represented by the followinggeneral formula (I) or a pharmaceutically acceptable salt thereof

wherein each symbol has the following meaning, D: H-pyrazol-3-yl whichmay have 1 to 2 substituents selected from the group consisting of-lower alkyl(“Alk”), -lower alkenyl, -lower alkynyl, halogeno-loweralkyl-, -cycloalkyl, —O-Alk, —COO-Alk and -halogen atom(“Hal”), n: 0, B:1,4-phenylene, X: —NH—CO—, and A: aryl which may have one or moresubstituents of group F; mono- or di-cyclic fused heteroaryl selectedfrom the group consisting of thienyl, furanyl, pyrrolyl, imidazolyl,pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, tetrazolyl,triazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,indolyl, isoindolyl, isoquinolyl, quinolyl, quinoxanyl, phthalazinyl,imidazo[1,2-a]pyridyl, quinazolinyl and cinnolinyl which may have one ormore substituents of group F; cycloalkyl; or Alk, wherein the F groupis: -Alk, -lower alkenyl, -lower alkynyl, -Hal, —NH₂, —NH(Alk),—N(Alk)₂, —NO₂, —CN, —OH, —O-Alk, —O—CO-Alk, —SH, —S-Alk, —COO-Alk,—CO-Alk, —CONH₂, —CONH(Alk), —CON(Alk)₂, —SO-Alk, —SO₂-Alk, and —SO₂NH₂with the proviso that when D is 1H-pyrazol-3-yl or5-methyl-1H-pyrazol-3-yl, A is a group other than methyl.
 21. Thepyrazole compound or pharmaceutically acceptable salt thereof accordingto claim 20, wherein D is 1H-pyrazol-3-yl which may have 1 to 2substituents selected from -Alk, halogeno-lower alkyl- and —COO-Alk, andA is phenyl which may have one or more substituents selected from thegroup consisting of Alk, -Hal, —NH₂, —N(Alk)₂, —NO₂, —CN, —OH, —O-Alkand —COO-Alk; mono- or di-cyclic fused heteroaryl selected from thegroup consisting of thienyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl,tetrazolyl, triazolyl, thiadiazolyl, pyridyl, pyrazinyl and isoquinolyl,which may be substituted with one or more Alk; cycloalkyl; or Alk. 22.The pyrazole compound or pharmaceutically acceptable salt thereofaccording to claim 20, wherein D is 1H-pyrazol-3-yl substituted with atleast one trifluoromethyl group.
 23. The pyrazole compound orpharmaceutically acceptable salt thereof according to claim 20, whereinA is monocyclic heteroaryl selected from the group consisting ofthiazolyl, thiadiazolyl, thienyl and pyridyl, which may be substitutedwith one or more Alk.
 24. A pharmaceutical composition which comprises apharmaceutically effective amount of a pyrazole compound represented bythe following general formula (I′) or a pharmaceutically acceptable saltthereof and a pharmaceutically acceptable carrier

wherein each symbol has the following meaning, D: 1H-pyrazol-3-yl whichmay have 1 to 2 substituents selected from the group consisting of -Alk,-lower alkenyl, -lower alkynyl, halogeno-lower alkyl-, -cycloalkyl,—O-Alk, —COO-Alk and -Hal, n: 0, B: 1,4-phenylene, X: —NH—CO—, and A:aryl which may have one or more substituents of group F; mono- ordi-cyclic fused heteroaryl selected from the group consisting ofthienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl,isothiazolyl, oxazolyl, isoxazolyl, tetrazolyl, triazolyl, thiadiazolyl,pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl,isoquinolyl, quinolyl, quinoxanyl, phthalazinyl, imidazo[1,2-a]pyridyl,quinazolinyl and cinnolinyl which may have one or more substituents ofgroup F; cycloalkyl; or Alk, wherein the F group is: -Alk, -loweralkenyl, -lower alkynyl, -Hal, —NH₂, —NH(Alk), —N(Alk)₂, —NO₂, —CN, —OH,—O-Alk, —O—CO-Alk, —SH, —S-Alk, —COO-Alk, —CO-Alk, —CONH₂, —CONH(Alk),—CON(Alk)₂, —SO-Alk, —SO₂-Alk, and —SO₂NH₂, with the proviso that when Dis 1H-pyrazol-3-yl or 5-methyl-1H-pyrazol-3-yl, A is a group other thanmethyl.
 25. The pharmaceutical composition according to claim 24,wherein D is 1H-pyrazol-3-yl substituted with at least onetrifluoromethyl group.
 26. The pharmaceutical composition according toclaim 24, wherein A is monocyclic heteroaryl selected from the groupconsisting of thiazolyl, thiadiazolyl, thienyl and pyridyl, which may besubstituted with Alk.
 27. A method for treating bronchial asthma, whichcomprises administering a pharmaceutical composition comprising apyrazole compound represented by the following general formula (I′)

wherein each symbol has the following meaning, D: 1H-pyrazol-3-yl whichmay have 1 to 2 substituents selected from the group consisting of -Alk,-lower alkenyl, -lower alkynyl, halogeno-lower alkyl-, -cycloalkyl,—O-Alk, —COO-Alk and -Hal, n: 0, B: 1,4-phenylene, X: —NH—CO—, and A:aryl which may have one or more substituents of group F; mono- ordi-cyclic fused heteroaryl selected from the group consisting ofthienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl,isothiazolyl, oxazolyl, isoxazolyl, tetrazolyl, triazolyl, thiadiazolyl,pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl,isoquinolyl, quinolyl, quinoxanyl, phthalazinyl, imidazo[1,2-a]pyridyl,quinazolinyl and cinnolinyl which may have one or more substituents ofgroup F; cycloalkyl; or Alk, wherein the F group is: -Alk, -loweralkenyl, -lower alkynyl, -Hal, —NH₂, —NH(Alk), —N(Alk)₂, —NO₂, —CN, —OH,—O-Alk, —O—CO-Alk, —SH, —S-Alk, —COO-Alk, —CO-Alk, —CONH₂, —CONH(Alk),—CON(Alk)₂, —SO-Alk, —SO₂-Alk, and —SO₂NH₂, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier, inan effective amount for treating said disease in a patient sufferingfrom or susceptible to said disease.
 28. A method for treatingrheumatoid arthritis, which comprises administering a pharmaceuticalcomposition comprising a pyrazole compound represented by the followinggeneral formula (I′)

wherein each symbol has the following meaning, D: 1H-pyrazol-3-yl whichmay have 1 to 2 substituents selected from the group consisting of -Alk,-lower alkenyl, -lower alkynyl, halogeno-lower alkyl-, -cycloalkyl,—O-Alk, —COO-Alk and -Hal, n: 0, B: 1,4-phenylene, X: —NH—CO—, and A:aryl which may have one or more substituents of group F; mono- ordi-cyclic fused heteroaryl selected from the group consisting ofthienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl,isothiazolyl, oxazolyl, isoxazolyl, tetrazolyl, triazolyl, thiadiazolyl,pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl,isoquinolyl, quinolyl, quinoxanyl, phthalazinyl, imidazo[1,2-a]pyridyl,quinazolinyl and cinnolinyl which may have one or more substituents ofgroup F; cycloalkyl; or Alk, wherein the F group is: -Alk, -loweralkenyl, -lower alkynyl, -Hal, —NH₂, —NH(Alk), —N(Alk)₂, —NO₂, —CN, —OH,—O-Alk, —O—CO-Alk, —SH, —S-Alk, —COO-Alk, —CO-Alk, —CONH₂, —CONH(Alk),—CON(Alk)₂, —SO-Alk, —SO₂-Alk, and —SO₂NH₂, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier, inan effective amount for treating said disease in a patient sufferingfrom or susceptible to said disease.
 29. The method for treatingbronchial asthma according to claim 27, wherein D is 1H-pyrazol-3-ylwhich may have 1 to 2 substituents selected from the group consisting of-Alk, -lower alkenyl, -lower alkynyl, halogeno-lower alkyl-,-cycloalkyl, —O-Alk, —COO-Alk and -Hal, B is 1,4-phenylene, and X is—NH—CO—.
 30. The method for treating rheumatoid arthritis according toclaim 28, wherein D is 1H-pyrazol-3-yl which may have 1 to 2substituents selected from the group consisting of -Alk, -lower alkenyl,-lower alkynyl, halogeno-lower alkyl-, -cycloalkyl, —O-Alk, —COO-Alk and-Hal, B is 1,4-phenylene, and X is —NH—CO—.